The goal of this SBIR project is to complete the preclinical studies required to submit an IND application for a promising new therapeutic (SH7139) for non-Hodgkin's lymphoma so as to be able to advance this drug into clinical trials. SH7139 is a selective high affinity ligand (SHAL) that was designed to target a unique site on HLA-DR10, a protein receptor found on the surface of B-cell lymphocytes. HLA-DR10 is over-expressed 10- 100 fold in many B-cell derived lymphomas and leukemias. The results we obtained from a previously funded NIH/NCI program project grant showed that SH7139 targets the HLA-DR10 receptor with very high affinity (Kd ~ 23 pM) and that it selectively kills only cells over-expressing HLA-DR-10. In a Raji xenograft mouse model, 69% of the animals treated with 55g/kg of SH7139 experienced a permanent cure;that is, the tumors disappeared within 30 days after treatment and did not reoccur during the remainder of the life of the animal. In addition, no adverse side effects were observed in the animals, even when the dose was increased by 2000- fold. The specific aims proposed in Phase I of this SBIR are to: (1) synthesize, chemically characterize and test the biological activity of a SH7139 standard;(2) scale up the synthesis of SH7139 to multi-gram quantities and check its purity, physical characteristics and biological activity against that of the standard compound;and (3) determine the dose of SH7139 that provides the highest cure rate in a xenograft model and use this information to define the doses used in the preclinical, toxicology and safety studies that will be performed in Phase II of the SBIR. Following the completion of the Phase I SBIR study, we will submit a Phase II SBIR proposal in which the scale-up synthesis protocol and dose information obtained in Phase I will be used to produce GMP SH7139 and complete the remaining pre-clinical, toxicology and safety studies that are necessary to submit the IND application. If successful, this effort will develop a more effective first-line therapy for advanced NHL, one that is systemically non-toxic and provides cures rather than incremental increases in the delay of cancer progression. The advantages of SH7139 over the FDA approved NHL drugs and many others in development are: (1) SH7139 represents a dramatic departure from current B-cell lymphoma therapeutics, including Rituxan. In addition to being highly specific in targeting and killing only tumor cells, cures (not complete responses) are achieved in the majority of the treated individuals (mice bearing xenografts), (2) Fewer side effects would be expected, because only those cells that are over-expressing HLA- DR10 are targeted and normal cells are not affected. (3) Because SH7139 is a targeting agent, it can also be used as a companion diagnostic to identify those patients for whom this treatment would be most likely to be effective, thereby minimizing the risks associated with therapy. (4) The low cost of synthesis of this drug should reduce NHL therapy costs significantly, enabling treatments to become more widely available and accessible. PUBLIC HEALTH RELEVANCE: There is a public health need to develop more efficacious, less toxic and more cost effective treatments for advanced cancers. This project addresses these issues by proposing studies needed to advance into the clinic a promising new targeting agent and therapeutic for patients with advanced Non-Hodgkin's lymphoma, which our preliminary results suggest is remarkable and is likely to improve patient survival and reduce side effects and treatment costs significantly.